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Glycemic control, drug regimen interaction influence mortality risk in type 2 diabetes
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Adults with type 2 diabetes who achieve low HbA1c targets may have an increased risk for death, particularly when treated with regimens associated with hypoglycemia, compared with adults with moderate HbA1c levels, epidemiologic data show.
“Contrary to commonly held beliefs, we don’t yet fully understand the association between glucose control and some serious outcomes, including mortality,” Craig J. Currie, PhD, professor of applied pharmacoepidemiology at the Cochrane Institute of Primary Care and Public Health, Cardiff University, U.K., told Endocrine Today. “We need to investigate thoroughly the epidemiology of outcome in relation to glucose control, and we need to use insulin cautiously in people with type 2 diabetes.”
Currie and colleagues evaluated data from the U.K. Clinical Practice Research Datalink and the Hospital Episode Statistics on 131,315 adults with type 2 diabetes prescribed glucose-lowering therapy as monotherapy or as dual therapy with metformin, identified between January 2004 and December 2013, to characterize risks for all-cause mortality across the range of achieved HbA1c targets. Researchers also sought to determine whether the pattern varied in alternative regimens with differing risks for hypoglycemia. Participants were followed until January 2015.
Achieved HbA1c was categorized as low (< 7%), moderate ( 7% to < 8%), high ( 8% to < 9.5%) and very high ( 9.5%). Regimen categories included metformin monotherapy (n = 76,821); regimens with a low risk for hypoglycemia (n = 101,740); sulfonylurea monotherapy (n = 14,834); insulin monotherapy (n = 6,827); regimens with a higher hypoglycemia risk, excluding insulin (n = 50,094); and regimens with a higher hypoglycemia risk, including insulin (n = 66,046).
Among the cohort, there were 6,646 deaths for an overall crude mortality rate of 17.7 deaths per 1,000 person-years of exposure.
The overall adjusted HRs were 1.16 (95% CI, 1.06-1.18) for low HbA1c, 1.18 (95% CI, 1.07-1.32) for high HbA1c and 1.16 (95% CI, 1.03-1.32) for very high HbA1c compared with moderate HbA1c.
Compared with participants with moderate HbA1c, participants with low HbA1c had a higher risk for all-cause mortality with insulin monotherapy (HR = 1.47; 95% CI, 1.25-1.72) and with regimens with high hypoglycemia risk whether excluding insulin (HR = 1.24; 95% CI, 1.13-1.35) or including insulin (HR = 1.28; 95% CI, 1.18-1.37). Participants with high and very high HbA1c did not have an increased risk for mortality when using sulfonylurea monotherapy, insulin monotherapy or regimens with a higher risk of hypoglycemia. The risk for all-cause mortality was significantly increased with metformin monotherapy when participants had high (HR = 1.37; 95% CI, 1.09-1.72) and very high HbA1c (HR = 1.7; 95% CI, 1.28-2.26); significantly increased mortality risk was also found among participants prescribed regimens with a low risk for hypoglycemia when they had high (HR = 1.27; 95% CI, 1.04-1.56) and very high HbA1c (HR = 1.45; 95% CI, 1.12-1.89) compared with moderate HbA1c.
“Treatment guidelines generally recommend therapeutic strategies that aim for low levels of glucose control, on the understanding that it reduces risk of macrovascular complications, such as coronary artery disease and stroke,” Currie said in a press release. “Contrary to this belief, our findings show persuasively that there is an association with increased mortality risk and what is considered to be good glucose control, or low HbA1c.” – by Amber Cox
For more information:
Craig J. Currie, PhD, can be reached at currie@cardiff.ac.uk.
Disclosures: Currie reports he is employed by and a director of Pharmatelligence. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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It has been known that hypoglycemia can kill since the discovery of insulin nearly a century ago. There are now numerous reports of an association between hypoglycemia and death in diabetes, there is statistical evidence that the association is not entirely attributable to confounding by comorbidities, and there are 21st century reports of hypoglycemic mortality rates of 7%, 8% and 10% or more in type 1 diabetes (Cryer et al. Hypoglycaemic mortality in diabetes. 2017. Available at: http://ihsgonline.com/hypoglycaemia/hypoglycaemic-mortality-in-diabetes/. Accessed November 17, 2017). There is also consistent evidence that lower HbA1c levels are associated with higher rates of severe hypoglycemia and with higher rates of CGM-determined rates of glucose concentrations less than 50 mg/dL (2.8 mmol/L; van Beers CAJ, et al. J Diabetes Complications. 2017;doi:10.1016/j.jdiacomp.2017.09.005). The finding of Currie and colleagues that lower HbA1c levels (< 7%) were associated with increased mortality compared with higher HbA1c levels in patients with type 2 diabetes at higher risk for hypoglycemia, particularly those treated with insulin, is entirely consistent with the body of evidence that iatrogenic hypoglycemia is a risk factor for death in diabetes. Collectively these findings underscore the importance of careful balancing of benefits and potential harms in the selection of goals in patients with diabetes treated with insulin, a sulfonylurea, or a glinide.
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